Are KRAS Inhibitors Poised To Cure Cancer?

By Aditi Shivarkar, insightSLICE

KRAS inhibitors are a class of drugs designed to target the KRAS gene, which is a crucial component of cell signaling pathways involved in cell growth and division. KRAS is frequently mutated in various cancers, including pancreatic, colorectal, and lung cancers, making it one of the most commonly altered oncogenes.

These inhibitors are of great importance because KRAS mutations drive tumor growth and contribute to cancer development, making them attractive therapeutic targets. Historically, KRAS was deemed "undruggable" due to the nature of the KRAS protein and its complex interactions. However, in recent years, there have been significant advancements in drug development technologies and computational biology, enabling scientists to better understand KRAS biology and identify potential drug targets. These advancements have led to the discovery of novel strategies to inhibit KRAS signaling, such as covalent inhibitors and allosteric inhibitors.

By targeting KRAS, these inhibitors aim to block the aberrant signaling that promotes cancer cell proliferation, thereby suppressing tumor growth and potentially improving patient outcomes. As a result, KRAS inhibitors have surged as promising candidates in the ongoing efforts to develop more effective and personalized treatments for various cancers with KRAS mutations, filling a critical gap in oncology therapeutics.

The accelerated approval of Amgen’s KRAS G12C inhibitor, sotorasib (Lumakras), by the FDA in May 2021 for advanced or metastatic KRAS G12C-mutated non-small cell lung cancer exemplifies the increasing adoption of targeted therapies in oncology. It became the first approved KRAS inhibitor and marked a milestone for the field, opening up an exciting opportunity for biopharmaceutical companies. Let’s take a closer look at our new analysis of the KRAS inhibitors market.

Prevalence of KRAS-Mutant Cancers

KRAS mutations are among the most common genetic alterations in various cancer types. For instance, in pancreatic cancer, approximately 90% of cases have KRAS mutations, while in colorectal cancer, the prevalence is around 30%–45%. Lung cancer is another area where KRAS mutations are frequent, especially in adenocarcinoma cases. As awareness of the impact of KRAS mutations on cancer progression grows, the demand for targeted therapies like KRAS inhibitors rises. This increasing prevalence of KRAS-mutant cancers creates a significant market opportunity for pharmaceutical companies to develop and commercialize effective KRAS inhibitors. For instance, a study published in the Journal of Thoracic Oncology in 2018 reported that KRAS mutations were present in 32.5% of non-small cell lung cancer (NSCLC) cases, highlighting the relevance of KRAS inhibitors in treating this subset of lung cancer patients.

Based on indication, we segmented our analysis into NSCLC, colorectal cancer (CRC), pancreatic cancer, and other indications (ovarian cancer, hematological malignancies). Among these, NSCLC is the largest segment due to its high prevalence and the significant role of KRAS mutations in driving NSCLC development. KRAS mutations are one of the most common genetic alterations in NSCLC, with the G12C mutation being the most frequently observed subtype. As awareness of the importance of KRAS mutations in NSCLC grows, there is an increasing demand for targeted therapies like KRAS inhibitors to address this subset of patients. The approval of KRAS G12C inhibitors, such as Amgen's sotorasib (Lumakras), has further fueled interest in the development and adoption of KRAS inhibitors for NSCLC treatment.

NSCLC is a heterogeneous disease, and not all patients with KRAS mutations may respond equally to KRAS inhibitors. Biomarker-driven approaches are gaining prominence to identify patients who are most likely to benefit from KRAS inhibitor therapy. Genetic testing for specific KRAS mutations and other relevant biomarkers is crucial to identify suitable candidates for treatment. This personalized medicine approach aims to improve treatment efficacy, minimize adverse effects, and make better-informed decisions in selecting patients for clinical trials and therapeutic interventions.

Covalent Vs. Non-covalent

Covalent KRAS inhibitors have gained significant attention, particularly due to the success of covalent inhibitors such as Lumakras and Mirati Therapeutics' adagrasib in clinical trials. Covalent inhibitors are considered a promising therapeutic class for their ability to form irreversible bonds with the target protein, potentially leading to enhanced target specificity and prolonged inhibition.

While covalent inhibitors have shown promise, research and development in the non-covalent KRAS inhibitors segment have not slowed down. Non-covalent inhibitors form reversible interactions with the target, allowing for more flexibility in drug design and potential reduction of off-target effects. The development of non-covalent KRAS inhibitors is an active area of investigation, with several compounds in preclinical and early clinical stages. As these inhibitors progress in development and demonstrate their efficacy, they may carve out a significant share of the KRAS inhibitors market.

Monotherapy Vs. Combination Therapy

KRAS-mutant cancers are known for their complexity and ability to develop resistance to single-agent therapies over time. To overcome this challenge, researchers and clinicians have increasingly explored combination therapies, which involve the simultaneous use of multiple drugs targeting different pathways in cancer cells. By combining KRAS inhibitors with other targeted therapies, immunotherapies, or standard chemotherapy, these regimens can create synergistic effects, enhance treatment efficacy, and potentially delay or prevent the emergence of drug resistance. The success of certain combination therapies in clinical trials, along with the urgency to improve patient outcomes in difficult-to-treat KRAS-mutant cancers, has led to the dominance of the combination therapy approach, as opposed to the monotherapy approach.

Three key industry trends are:

• Combinations with Immune Checkpoint Inhibitors (ICIs): One prominent trend is the investigation of KRAS inhibitors in combination with immune checkpoint inhibitors (ICIs). Preclinical and clinical studies have shown that combining KRAS inhibitors with ICIs, such as anti-PD-1 or anti-CTLA-4 antibodies, can enhance the anti-tumor immune response. The rationale behind this combination is that KRAS inhibitors can potentially modulate the tumor microenvironment and increase the visibility of cancer cells to the immune system, making them more susceptible to immune attack. Several ongoing clinical trials are evaluating the efficacy and safety of this combination strategy in various KRAS-mutant cancers.
• Dual KRAS Inhibition: Another trend in combination therapy involves using two or more KRAS inhibitors simultaneously. One approach is to combine covalent and non-covalent KRAS inhibitors to target different conformations of the KRAS protein and achieve a more comprehensive inhibition of KRAS signaling. Another strategy is to combine KRAS inhibitors with downstream pathway inhibitors to block multiple points in the KRAS signaling cascade. Dual KRAS inhibition aims to enhance the potency of the treatment and potentially overcome resistance mechanisms that may arise from single-agent therapies.
• Personalized and Biomarker-Driven Approaches: With the growing recognition of the heterogeneity of KRAS-mutant cancers, there is an increasing focus on personalized and biomarker-driven combination therapy approaches. Identifying specific biomarkers that can predict patient response to certain combinations is crucial for optimizing treatment outcomes. Biomarkers may include specific KRAS mutations, other genetic alterations, or molecular characteristics of the tumor. Tailoring combination therapies based on individual patient profiles aims to improve treatment response rates and minimize unnecessary side effects. Companies such as Mirati Therapeutics have been studying biomarkers to better understand adagrasib's efficacy in different patient populations.

Geographic Markets

Geographically, the market is segmented into North America, Europe, APAC, Middle East and Africa, and South America. North America is likely the largest segment in the global KRAS inhibitors market. Several factors contribute to its dominance:

• North America has a well-established healthcare infrastructure and advanced research and development capabilities, fostering the early adoption and development of innovative therapies like KRAS inhibitors.
• The region has a high incidence of KRAS-mutant cancers, particularly in the United States, where non-small cell lung cancer, colorectal cancer, and pancreatic cancer are prevalent. This substantial patient pool drives the demand for targeted therapies such as KRAS inhibitors.
• Regulatory agencies like the U.S. FDA have been proactive in expediting the approval process for promising KRAS inhibitors, enabling faster market access.
• There is a strong presence of academic institutions, research centers, and pharmaceutical and biotechnology companies conducting clinical trials and commercializing novel KRAS inhibitors.
• North America has been at the forefront of precision medicine. Researchers and healthcare providers are incorporating genetic testing into clinical practice to identify patients who are most likely to respond to KRAS inhibitors, optimizing treatment efficacy, and minimizing unnecessary side effects.

Competitive Insights

Here are some key strategies for companies developing KRAS inhibitors:

• Investment in R&D: Companies have been actively investing in research and development to expand their pipeline of KRAS inhibitors. For example, Amgen has been conducting clinical trials for its KRAS G12C inhibitor, sotorasib (Lumakras), for various cancer types to explore its potential beyond NSCLC.
• Strategic Collaborations and Partnerships: Collaboration with other pharmaceutical companies or academic institutions allows access to complementary expertise and resources. Mirati Therapeutics partnered with Novartis to co-develop adagrasib (MRTX849), combining their efforts to bring this KRAS G12C inhibitor to market.
• Combination Therapies: Exploring combination therapies with KRAS inhibitors and other agents is a promising strategy. Amgen and Mirati Therapeutics, among others, are conducting clinical trials to assess the potential benefits of combining their KRAS inhibitors with other treatments.
• Pricing: As with any innovative therapy, cost and reimbursement considerations pose challenges. Striking a balance between pricing and accessibility will be crucial for widespread adoption and affordability of KRAS inhibitors.

About The Author:

Aditi Shivarkar is principal consultant at insightSLICE, a market intelligence and strategy consulting company. She has been a part of the research industry for 13 years. She joined insightSLICE in 2021 and she works with clients to design studies that generate the data needed to answer their strategic market analysis, segmentation, brand equity, and pricing questions. She works across various domains, including healthcare, industrial automation, consumer goods, IT, and telecom.